叶酸缺乏导致神经管畸形(NTDs) 的发生机制尚不清楚。叶酸缺乏会引起 DNA 双链断裂，影响神经管的闭合及胎儿的生长发育，而这种代谢失衡的DNA损伤修复如何影响神经管闭合的机制并不清楚。课题组前期证实叶酸缺乏致基因组双链断裂（DSB）并与组蛋白甲基化修饰分布相关。叶酸缺乏下组蛋白修饰异常是否通过参与DNA损伤修复影响神经管闭合基因的转录并继而影响NTDs发生发展是本项目拟解决的科学问题。我们将利用分子生物学、细胞生物学研究明确组蛋白特异位点的修饰通过参与DNA损伤修复路径对神经管闭合关键通路产生影响; 探讨叶酸增补对上述路径神经管闭合通路的“补救效应”，并利用动物模型和临床标本对前述实验结果进行验证，探讨叶酸缺乏下DNA损伤修复途径对基因表达的调控作用,探寻叶酸缺乏导致NTDs的发病机理，研究结果也可对同类出生缺陷发生的表观遗传机制提供科学借鉴。

Abstract: The folate deficiency pathological mechanism of Neural tube defects (NTDs) is not yet fully understood. Folate deficiency induced DNA double - strand break (DSB) and resulted in NTDs. It is not known whether DNA damage response affect neural tube closure pathways by folate metabolic environment in early embryo development. Our previously study detected the correlation analysis of DSB hot spot distribution and histone methylation modification sites. This project to solve scientific problems is whether histone modifications involving in the DNA damage response affect gene transcription in folate deficiency and how these regulations influence the occurrence and development of NTDs . We will definite histone modifications involving in the DNA damage response selective regulation in growth pathway and investigate the effects of histone modificationson the regulation of growth gene expression through multifold molecular and cellular biology assays. Furthermore, We will be revealed the effects of folic acid supplementation on the above-mentioned integration pathway and the intervention mechanism of key neural tube closure pathways. At the same time, we will make further study on function and mechanism of histone modifications in the occurrence and development of NTDs. This project aim to investigate the functions of DNA damage response in gene transcription regulation by folate deficiency from the perspective of epigenetics for further analyzes the etiology of NTDs. The results may provide scientific reference for the epigenetic mechanism of similar birth defects in the future.